We propose a pharmacoepidemiology study of maternal depression and prenatal antidepressant medication use to address concerns regarding their association with the risk of autism spectrum disorder (ASD) in children. This study will cost efficiently evaluate this relationship via use of a large, electronic medical record database, the Clinical Practice Research Datalink (CPRD). The CPRD is the most widely used resource for drug safety research in the world and has the ability to link mother and baby records to study exposures during pregnancy and outcomes in the offspring. In a preliminary analysis, we identified ~471,000 eligible mother-baby pairs and ~4,500 ASD cases, with a mean of 6.5 years of recorded history for the mothers and mean of 10 years of follow-up for the children. The proposed study, which will be the largest study conducted on this topic to date, will have two parts: 1) a cohort study and 2) a nested bidirectional case-crossover sibling study. To separate the drug effect from that of underlying disease, we will consider three exposure categories; 1) Antidepressant and Depression Exposed (~16,400 mother-baby pairs), 2) Depression Only Exposed (~34,000 mother-baby pairs), and 3) Antidepressant Only Exposed (~9,000 mother-baby pairs), compared to a matched (4:1) unexposed cohort of women who have neither depression nor antidepressant medications. Defining the exposed cohort in this way will allow us to independently evaluate the effects of depression, the combined effect of antidepressants and depression, and the effect of antidepressants in the absence of depression on the risk of ASD in offspring. We will also conduct a novel 'within-mother-between-pregnancy' nested case-crossover sibling analysis to compare prenatal antidepressant medication exposure among ASD cases to that of non-ASD siblings born to the same mother. This sibling analysis will control for genetic and environmental risk factors for ASD, as well as maternal predisposition to depression. We will examine confounding for the wide variety of medical and behavioral covariates available in the CPRD using matching, stratification, and multivariable analysis. Our research team is comprised of experts in pharmacoepidemiology drug safety studies, with demonstrated experience in studies on depression, antidepressants, prenatal exposures and outcomes in offspring. We have immediate access to the CPRD data and the PI has >25 years of experience in studies using the CPRD. Other strengths of our proposed research include its large number of mother-baby pairs with long follow-up time, use of existing medical records (avoiding concerns of patient recall), the richness of covariate information for confounder control, and the nested case-crossover sibling analysis to closely control for genetic and environmental risk factors. The public health contribution of this project is to quickly inform the safety profile of antidepressant medications and the broader debate on the use of these medications during pregnancy with respect to the growing number of children diagnosed with ASD.